Publications by authors named "Masaaki Inoue"

35 Publications

Two Cases of Bronchial Artery Racemose Hemangioma Successfully Treated with Bronchial Artery Embolization.

J Nippon Med Sch 2021 Nov 26. Epub 2021 Nov 26.

Department of Emergency and Critical Care Medicine, Nippon Medical School.

Rupture of a racemose hemangioma causing dilatation and tortuosity of the bronchial artery can result in massive bleeding and respiratory failure. Bronchial artery embolization (BAE) can treat this life-threatening condition, as we show in two cases. The first case was of an 89-year-old female complaining of sudden-onset chest and back pain. Bronchial artery angiography demonstrated a racemose hemangioma with a 2 cm aneurysm. The second case was of a 50-year-old male with hemoptysis and dyspnea, eventually requiring intubation. Bronchial arteriography showed a racemose hemangioma and a bronchial artery-pulmonary arterial fistula. BAE was successfully performed in both cases, with no recurrent hemorrhage. Therapeutic interventions in bronchial artery racemose hemangiomas include lobectomy or segmentectomy, bronchial arterial ligation, and BAE. BAE should be considered as first-line therapy for bleeding racemose hemangiomas of the bronchial artery because of its low risk of adverse effects on respiratory status, minimal invasiveness, and faster patient recovery.
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http://dx.doi.org/10.1272/jnms.JNMS.2022_89-601DOI Listing
November 2021

Efficacy and safety of immune checkpoint inhibitor monotherapy in elderly patients with non-small cell lung cancer.

Aging Med (Milton) 2021 Mar 29;4(1):42-46. Epub 2021 Jan 29.

Department of Chest Surgery Shimonoseki City Hospital Shimonoseki Japan.

The efficacy and safety of immune checkpoint inhibitor (ICI) monotherapy in elderly patients with non-small cell lung cancer (NSCLC) remain unclear, especially in patients older than 80 years. We retrospectively reviewed the records of 10 patients older than 80 years with NSCLCs treated by ICIs. The median age was 85 years (range, 82-93 years), and 7 patients were men. The median length of follow-up was 13 months (range, 4.5-23 months). Eight patients had adenocarcinoma (3 of whom had exon 19 deletions), and two had squamous cell carcinoma. Expression of programmed cell death ligand 1 (PD-L1) was ≥ 50% in 3 patients, between 1% and 49% in 4 patients, < 1% in 1 patient, and undetected in 2 patients. Patients with undetected PD-L1 underwent transbronchial lung biopsy. Performance status was graded zero, one, and two in two, seven, and one patients, respectively. First-, second-, and third-line treatments were administered to three, three, and four patients, respectively. The 2-year overall survival rate was 30.0% (median, 285 days). Time to treatment failure rate on the 2 years was 10.0% (median, 167 days). One patient achieved a partial response, and one achieved a complete response. ICI-associated adverse events occurred in five patients. In summary, ICIs were effective in some patients older than 80 years; however, some experienced adverse effects. Elderly patients must be selected carefully for ICI treatment.
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http://dx.doi.org/10.1002/agm2.12147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954839PMC
March 2021

Novel prospective umbrella-type lung cancer registry study for clarifying clinical practice patterns: CS-Lung-003 study protocol.

Thorac Cancer 2021 03 12;12(5):725-731. Epub 2021 Jan 12.

Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Introduction: Conventional cancer registries are suitable for simple surveillance of cancer patients, including disease frequency and distribution, demographics, and prognosis; however, the collected data are inadequate to clarify comprehensively diverse clinical questions in daily practice.

Methods: We constructed an umbrella-type lung cancer patient registry (CS-Lung-003) integrating multiple related prospective observational studies (linked studies) that reflect clinical questions about lung cancer treatment. The primary endpoint of this registry is to clarify daily clinical practice patterns in lung cancer treatment; a key inclusion criterion is pathologically diagnosed lung cancer. Under this registry, indispensable clinical items are detected in advance across all active linked studies and gathered prospectively and systematically to avoid excessive or insufficient data collection. Researchers are to input information mutually, irrespective of the relevance to each researcher's own study. Linked studies under the umbrella of the CS-Lung-003 registry will be updated annually with newly raised clinical questions; some linked studies will be newly created, while others will be deleted after the completion of the analysis. Enrollment began in July 2017.

Discussion: We successfully launched the umbrella-type CS-Lung-003 registry. Under this single registry, researchers collaborate on patient registration and data provision for their own and other studies. Thus, the registry will produce results for multiple domains of study, providing answers to questions about lung cancer treatment raised by other researchers. Through such analysis of each linked study, this registry will contribute to the comprehensive elucidation of actual daily practice patterns in lung cancer treatment.

Key Points: CS-Lung-003 registry directly integrates multiple linked studies created under the umbrella of this cancer registry to solve various clinical questions regarding daily practice patterns of lung cancer treatment.
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http://dx.doi.org/10.1111/1759-7714.13789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919112PMC
March 2021

Impact of HER2 expression on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS study subset analysis.

Lung Cancer 2020 12 1;150:83-89. Epub 2020 Oct 1.

Department of Respiratory Medicine, Okayama University Hospital, Japan.

Objectives: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC); however, a biomarker to predict their efficacy has not been established. Although human epidermal growth factor receptor-2 (HER2) aberrations constitute a potential mechanism for acquired resistance to EGFR-TKIs, the impact of HER2 on EGFR-TKI treatment outcomes has not been systematically evaluated. In this post-hoc subgroup study, we examined the impact of HER2 on the effect of EGFR-TKIs in patients with NSCLC harboring EGFR mutations.

Materials And Methods: Of 1126 patients with NSCLC enrolled into a prospective cohort study (HER2-CS study), we analyzed data of 356 (32 %) patients with EGFR-mutant tumors. HER2 protein expression levels were determined by immunohistochemistry (IHC) with the gastric cancer criteria. Patients were divided either to an HER2-P group (HER2-IHC2+/3+) or an HER2-N group (HER2-IHC0/1+). We primarily assessed differences in the time-to-treatment failure (TTF) of EGFR-TKI between the groups.

Results: The HER2 scoring was as follows: IHC0 (n = 76, 21 %), IHC1+ (n = 199, 56 %), IHC2+ (n = 72, 20 %), and IHC3+ (n = 9, 3 %). The patients' demographics were similar in the HER2-P and HER2-N groups. The HER2-P group showed a significantly shorter EGFR-TKI TTF than the HER2-N group (hazard ratio [HR]: 1.657, 95 % confidence interval [CI]: 1.076-2.552; median: 13.3 vs. 19.1 months). The magnitude of the negative impact of TTF was especially dependent on performance status (PS). HER2 expression significantly deteriorated the TTF in the subgroup with PS 2 (HR: 5.497, 95 % CI: 1.510-20.02), but not in that with better PS (HR: 1.437, 95 % CI: 0.899-2.298) (p = 0.015).

Conclusion: In the current cohort, HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs, the effect of which was PS dependent.
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http://dx.doi.org/10.1016/j.lungcan.2020.09.024DOI Listing
December 2020

Mortality related to drug-resistant organisms in surgical sepsis-3: an 8-year time trend study using sequential organ failure assessment scores.

Eur J Clin Microbiol Infect Dis 2021 Mar 21;40(3):535-540. Epub 2020 Sep 21.

Department of Surgery/Chest Surgery, Shimonoseki City Hospital, 1-13-1 Koyo-cho, Shimonoseki, 750-8520, Japan.

The difference in sequential organ failure assessment (SOFA) scores from the baseline to sepsis is a known predictor of sepsis-3 outcome, but the prognostic value of drug-resistant organisms for mortality is unexplained. We employed sepsis stewardship and herein report an observational study. Study subjects were patients admitted to the Departments of Surgery/Chest Surgery from 2011 through 2018 with a diagnosis of sepsis and a SOFA score of 2 or more. Our sepsis stewardship methods included antimicrobial and diagnostic stewardship and infection control. We determined the primary endpoint as in-hospital death and the secondary endpoint as the annual trend of the risk-adjusted mortality ratio (RAMR). For mortality, we performed logistic regression analysis based on SOFA score, age, sex, comorbid disease, and the presence of methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum beta-lactamase inhibitor-producing bacteria. In a total of 457 patients, two factors were significant predictors for fatality, i.e., SOFA score of 9 or more with an odds ratio (OR) 4.921 and 95% confidence interval [95% CI] 1.968-12.302 (P = 0.001) and presence of MRSA with an OR 1.83 and 95% CI 1.003-3.338 (P = 0.049). RAMR showed a decrease during the study years (P < 0.05). Early detection of MRSA may help patients survive surgical sepsis-3. Thus, MRSA-oriented diagnosis may play a role in expediting treatment with anti-MRSA antimicrobials.
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http://dx.doi.org/10.1007/s10096-020-04037-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892503PMC
March 2021

Mediastinal lymph node metastases in lung cancer presenting as pure ground-glass nodules: A surgical case report.

Int J Surg Case Rep 2020 28;70:5-7. Epub 2020 Mar 28.

Pathology, Shimonoseki City Hospital, Shimonoseki, Japan.

Introduction: Generally, lung cancer representing as Ground-glass nodules is associated with an early stage and good prognosis. However, we herein report a rare case of pure ground-glass nodules with mediastinal lymph node metastases.

Presentation Of Case: A 69-year-old man underwent video assisted thoracic surgery right upper lobectomy with mediastinal lymph node dissection due to multifocal Ground-glass nodules in the right upper lobe of the lung. Histopathologically, six lung adenocarcinomas were present simultaneously. Furthermore, we detected mediastinal lymph nodes metastases that contain micropapillary component. The lung lesion containing micropapillary component was a pure Ground-glass nodule that adjoining pulmonary bulla on CT findings.

Discussion: Generally, lung cancer presenting as pure ground-glass nodules is associated with an early stage and good prognosis. However, the necessity of evaluating the mediastinal lymph nodes in pure ground-glass nodules is controversial. It is reported that lung cancer adjoining the wall of a bulla tends to have a poor prognosis, even when small in size. Therefore, Ground-glass nodules with metastases might have a different pathogenesis than other nodules.

Conclusion: Adenocarcinoma appearing as pure Ground-glass nodules is associated with early stage lung cancer and a good prognosis. However, the findings in our patient indicate the importance and necessity of evaluating the mediastinal lymph nodes for metastases intraoperatively.
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http://dx.doi.org/10.1016/j.ijscr.2020.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183094PMC
March 2020

Thymic papillary adenocarcinoma coexisting with type A thymoma: A case report.

Int J Surg Case Rep 2019 30;57:142-144. Epub 2019 Mar 30.

Thoracic Surgery, Shimonoseki City Hospital, Shimonoseki, Japan.

Introduction: Thymic papillary adenocarcinoma is rare. Further, thymic papillary adenocarcinoma coexisting with type A thymoma is extremely rare. Surgery remains the only effective treatment for this disease.

Presentation Of Case: An 84-year-old Japanese woman presented to our institute due to abnormal chest computed tomography (CT) findings showing a 45 × 40 × 40-mm tumor located in the anterior mediastinum. A malignant tumor was suspected based on the CT findings and high serum levels of carcinoembryonic antigen. Mediastinal tumor resection was performed via video-assisted thoracic surgery through the left thoracic approach. This patient was discharged from our institute without any problems at six days post-operation.

Discussion: This report has three major implications. First, one of the tumors was papillary adenocarcinoma. Primary papillary adenocarcinoma of the thymus is exceedingly rare. Second, papillary adenocarcinoma and type A thymoma coexisted in this tumor. Third, epithelial thymic tumor should be resected completely, since complete resection has been reported to be associated with an improved prognosis.

Conclusion: We encountered a rare case of thymic papillary adenocarcinoma coexisting with type A thymoma.
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http://dx.doi.org/10.1016/j.ijscr.2019.03.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453800PMC
March 2019

Thoracoscopic Lung Lobectomy for a Lung Cancer Patient with Situs Inversus Totalis.

J UOEH 2018;40(3):237-241

Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Japan.

Situs inversus totalis is a rare clinical condition that represents a complete mirror image of the normal arrangement of the thoracic and abdominal viscera. There are very few reported cases of lung cancer patients with situs inversus totalis, but this condition requires particular care during surgery. A 61-year-old woman presented to our hospital with an abnormal shadow on chest radiography. Computed tomography revealed a 25×12 mm solitary pulmonary nodule in the left upper lobe (S2) and a complete mirror image of the normal organ arrangement, which findings met the criteria of situs inversus totalis. Preoperative examination revealed left upper lobe lung cancer (c-T1bN0M0 Stage IA), and surgery was planned for diagnosis and treatment. Before the surgery, three-dimensional CT images were reconstructed for a precise evaluation of the pulmonary vessels and bronchi. The nodule was microscopically diagnosed as adenocarcinoma from a frozen section obtained by wedge resection. We performed a left upper lobectomy with lymph node dissection using video-assisted thoracic surgery. The aortic arch was absent from the left thoracic cavity and the left lung was well lobulated into three lobes. Although it revealed a mirror image of the usual arrangement, we could accomplished in the usual procedure and process. Careful preoperative anatomical evaluation and perioperative handling are essential for the prevention of intraoperative injuries and complications in patients with situs inversus totalis.
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http://dx.doi.org/10.7888/juoeh.40.237DOI Listing
March 2019

Effect of pressure-controlled inverse ratio ventilation on dead space during robot-assisted laparoscopic radical prostatectomy: A randomised crossover study of three different ventilator modes.

Eur J Anaesthesiol 2018 04;35(4):307-314

From the Mizonokuchi Hospital, Teikyo University School of Medicine, Kanagawa (GH, KM, TA), Department of Anaesthesiology, Tokyo Medical University (YO), Department of R&D, Senko Medical Instrument Co., Ltd. (ST), Furrex Co., Ltd., Tokyo, Japan (KD), S.K.I. Net, Inc., Tokyo (MI), and Department of Anesthesiology and Intensive Care Medicine, International University of Health and Welfare, School of Medicine, Narita, Japan (KK).

Background: Pressure-controlled inverse inspiratory to expiratory ratio ventilation (PC-IRV) is thought to be beneficial for reducing the dead space volume.

Objective: To investigate the effects of PC-IRV on the components of dead space during robot-assisted laparoscopic radical prostatectomy (RLRP).

Design: A randomised crossover study of three different ventilator modes.

Setting: A single university hospital from September 2014 to April 2015.

Patients: Twenty consecutive study participants undergoing RLRP.

Interventions: Patients were ventilated sequentially with three different modes in random order for 30 min: volume control ventilation (VCV; inspiratory to expiratory ratio 0.5), pressure control ventilation (PCV; inspiratory to expiratory ratio 0.5) and PC-IRV. Inverse inspiratory to expiratory ratio was adjusted individually by observing the expiratory flow-time wave to prevent the risk of dynamic pulmonary hyperinflation.

Main Outcome Measures: The primary outcome included physiological dead space (VDphys), airway dead space (VDaw), alveolar dead space (VDalv) and shunt dead space (VDshunt). VDphys was calculated by Enghoff's method. We also analysed respiratory dead space (VDresp) and VDaw using a novel analytical method. Then, VDalv and VDshunt were calculated by VDalv = VDresp - VDaw and VDshunt = VDphys - VDresp, respectively.

Results: The VDphys/expired tidal volume (VTE) ratio in PC-IRV (29.2 ± 4.7%) was significantly reduced compared with that in VCV (43 ± 8.5%) and in PCV (35.9 ± 3.9%). The VDshunt/VTE in PC-IRV was significantly smaller than that in VCV and PCV. VDaw/VTE in PC-IRV was also significantly smaller than that in VCV but not that in PCV. There was no significant change in VDalv/VTE.

Conclusion: PC-IRV with the inspiratory to expiratory ratio individually adjusted by the expiratory flow-time wave decreased VDphys/VTE in patients undergoing RLRP.

Trial Registration: University Hospital Medical Information Network in Japan 000014004.
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http://dx.doi.org/10.1097/EJA.0000000000000732DOI Listing
April 2018

Protocol Design for the Bench to Bed Trial in Alectinib-Refractory Non-Small-Cell Lung Cancer Patients Harboring the EML4-ALK Fusion Gene (ALRIGHT/OLCSG1405).

Clin Lung Cancer 2016 11 2;17(6):602-605. Epub 2016 Jun 2.

Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Based on our preclinical study results, which showed that the activation of the hepatocyte growth factor/MET pathway is a potential mechanism of acquired resistance to alectinib, we launched the ALRIGHT (OLCSG1405 [alectinib-refractory non-small-cell lung cancer patients harboring the EML4-ALK fusion gene]), a phase II trial of the anaplastic lymphoma kinase (ALK)/MET inhibitor crizotinib in patients with non-small-cell lung cancer refractory to alectinib and harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. Patients with ALK-rearranged tumors who have developed disease progression during alectinib treatment will receive crizotinib monotherapy until disease progression or the occurrence of unacceptable toxicity. The primary endpoint is set as the objective response rate, assuming that a response in 50% of eligible patients will indicate potential usefulness and that 15% would be the lower limit of interest (1-sided α of 0.05, β of 0.20). The estimated accrual number of patients is 9. The secondary endpoints include progression-free survival, overall survival, adverse events, and patient-reported outcomes. We will also take tissue samples before crizotinib monotherapy to conduct an exploratory analysis of ALK and hepatocyte growth factor/MET expression levels and gene alterations (eg, mutations, amplifications, and translocations). We will obtain information regarding whether crizotinib, which targets not only ALK, but also MET, can truly produce efficacy with acceptable safety profiles in ALK non-small-cell lung cancer even in the alectinib-refractory setting.
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http://dx.doi.org/10.1016/j.cllc.2016.05.005DOI Listing
November 2016

A diagnostic marker for superficial urothelial bladder carcinoma: lack of nuclear ATBF1 (ZFHX3) by immunohistochemistry suggests malignant progression.

BMC Cancer 2016 10 18;16(1):805. Epub 2016 Oct 18.

Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, 1-Chome, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.

Background: Pathological stage and grade have limited ability to predict the outcomes of superficial urothelial bladder carcinoma at initial transurethral resection (TUR). AT-motif binding factor 1 (ATBF1) is a tumor suppressive transcription factor that is normally localized to the nucleus but has been detected in the cytoplasm in several cancers. Here, we examined the diagnostic value of the intracellular localization of ATBF1 as a marker for the identification of high risk urothelial bladder carcinoma.

Methods: Seven anti-ATBF1 antibodies were generated to cover the entire ATBF1 sequence. Four human influenza hemagglutinin-derived amino acid sequence-tagged expression vectors with truncated ATBF1 cDNA were constructed to map the functional domains of nuclear localization signals (NLSs) with the consensus sequence KR[X10-12]K. A total of 117 samples from initial TUR of human bladder carcinomas were analyzed. None of the patients had received chemotherapy or radiotherapy before pathological evaluation.

Results: ATBF1 nuclear localization was regulated synergistically by three NLSs on ATBF1. The cytoplasmic fragments of ATBF1 lacked NLSs. Patients were divided into two groups according to positive nuclear staining of ATBF1, and significant differences in overall survival (P = 0.021) and intravesical recurrence-free survival (P = 0.013) were detected between ATBF1+ (n = 110) and ATBF1- (n = 7) cases. Multivariate analysis revealed that ATBF1 staining was an independent prognostic factor for intravesical recurrence-free survival after adjusting for cellular grading and pathological staging (P = 0.008).

Conclusions: Cleavage of ATBF1 leads to the cytoplasmic localization of ATBF1 fragments and downregulates nuclear ATBF1. Alterations in the subcellular localization of ATBF1 due to fragmentation of the protein are related to the malignant character of urothelial carcinoma. Pathological evaluation using anti-ATBF1 antibodies enabled the identification of highly malignant cases that had been overlooked at initial TUR. Nuclear localization of ATBF1 indicates better prognosis of urothelial carcinoma.
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http://dx.doi.org/10.1186/s12885-016-2845-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070376PMC
October 2016

Phase II Study of the EGFR-TKI Rechallenge With Afatinib in Patients With Advanced NSCLC Harboring Sensitive EGFR Mutation Without T790M: Okayama Lung Cancer Study Group Trial OLCSG 1403.

Clin Lung Cancer 2017 03 9;18(2):241-244. Epub 2016 Jul 9.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as first-line therapy for patients with EGFR-mutated non-small-cell lung cancer (NSCLC) have shown a significantly better objective response rate and progression-free survival than platinum doublet therapy. However, acquired resistance often occurs within 12 months. One of the potential strategies for treating acquired resistance in NSCLC is the readministration of EGFR-TKIs, a strategy that has mainly been evaluated using gefitinib or erlotinib. The aim of the present study is to investigate the efficacy and safety of EGFR-TKI readministration with afatinib in patients with advanced NSCLC harboring activating EGFR mutations without T790M. The primary endpoint is progression-free survival. The secondary endpoints include the objective response rate, disease control rate, overall survival, toxicity, and quality of life. A total of 12 patients will be enrolled in this trial.
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http://dx.doi.org/10.1016/j.cllc.2016.07.003DOI Listing
March 2017

Single-incision laparoscopic surgery for gallstone ileus: An alternative surgical procedure.

Int J Surg Case Rep 2014 2;5(7):365-9. Epub 2014 May 2.

Department of Emergency Medicine, Shimonoseki City Hospital, 1-13-1 Koyo-Cho, Shimonoseki, Yamaguchi, Japan.

Introduction: Gallstone ileus (GI) results from the passage of a stone through a cholecystoenteric fistula, subsequently causing a bowel obstruction. The ideal treatment procedure for GI remains controversial.

Presentation Of Case: A 63-year-old female was admitted to our hospital following persistent nausea and vomiting for 7 days. Computed tomography revealed a partially calcified 4-cm circular object in the jejunum, and the proximal intestine was dilated, with concomitant pneumobilia. Based on the preoperative diagnosis of GI, enterotomy with stone extraction by single-incision laparoscopic surgery (SILS) was performed. The patient's postoperative course was uneventful, and the cholecystoduodenal fistula closed spontaneously 4 months after the surgery.

Discussion: Recent studies have reported that enterotomy with stone extraction alone is associated with better outcomes than with more invasive techniques. This case also suggests that enterotomy with stone extraction alone and careful postoperative follow-up is feasible for the management of GI. Although the use of laparoscopy in the management of GI has been described previously, laparoscopic surgery has not been widely performed, and SILS is not generally performed. When only this less demanding procedure is required, laparoscopic surgery, including SILS, can be a viable option.

Conclusion: SILS can be an alternative surgical procedure for the management of GI.
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http://dx.doi.org/10.1016/j.ijscr.2014.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064429PMC
June 2014

Pulmonary thromboembolism in lung surgery: use of unfractionated heparin.

Asian Cardiovasc Thorac Ann 2014 Jan 22;22(1):46-8. Epub 2013 Oct 22.

Department of Chest Surgery, Shimonoseki City Hospital, Shimonoseki, Japan.

Background: While thoracic surgeons occasionally encounter pulmonary thromboembolism, the use of unfractionated heparin may cause adverse effects.

Methods: We assessed a series of 323 consecutive pulmonary operations performed during 4 years from 2008 to 2011. All patients were given elastic stockings and intermittent pneumatic compression. During the first 2 years (2008-2009), none of the 169 patients received unfractionated heparin. In the second 2-year period (2010-2011), 135/154 patients received subcutaneous unfractionated heparin, either 5000 units (n = 37) or 2500 units (n = 93) twice daily for 3 days, or continuous intravenous unfractionated heparin (n = 5). The epidural catheters were withdrawn 6 h or more after unfractionated heparin use. Among patients without postoperative unfractionated heparin, 8 (42.1%) had a bleeding risk and 5 (26.3%) had limited operative time.

Results: One (0.6%) patient developed pulmonary thromboembolism during 2008-2009, but none had this complication during 2010-2011. The adverse outcome of intrathoracic bleeding occurred in one (2.7%) of the patients given 5000 units of unfractionated heparin, but no epidural hematomas occurred in these patients.

Conclusion: Patients undergoing thoracic surgery at low risk of bleeding may receive unfractionated heparin to prevent pulmonary thromboembolism while avoiding epidural complications.
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http://dx.doi.org/10.1177/0218492313475672DOI Listing
January 2014

Very long range quasi-Fourier spectroscopy for narrowband lasers.

Opt Express 2012 Dec;20(26):B566-73

NTT Access Network Service Systems Laboratories, NTT, 1-7-1 Hanabatake, Tsukuba, Ibaraki 305-0805, Japan.

The measurement of the spectral broadening, or temporal coherence property of very narrow linewidth lasers is not an easy task, while such a measurement is essential in any interferometric applications of the lasers. The beat note between two assumingly identical lasers only provides the convolutional spectral profile of the two lasers, but not characterizes the single laser. The delayed self-heterodyne interferometer (DSHI) would not be effective for kHz linewidth range because the finite delay cannot realize complete de-correlation. Here, we demonstrate, for the first time to our knowledge, the complete characterization of the modulus of the degree of coherence (DOC) of kHz linewidth lasers, with a self-referenced fashion where any other reference beam is not used, accordingly, characterize the spectral profile. The method is based on speckle statistical analysis of the Rayleigh scattering in the coherent fiber reflectometry, and would be a novel strong tool to characterize very narrow linewidth lasers.
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http://dx.doi.org/10.1364/OE.20.00B566DOI Listing
December 2012

Coherence characterization of narrow-linewidth beam by C-OFDR based Rayleigh speckle analysis.

Opt Express 2011 Oct;19(21):19790-6

NTT Access Network Service Systems Laboratories, NTT, 1-7-1, Hanabatake, Tsukuba, Ibaraki 305-0805, Japan.

A novel method for characterizing the amplitude of a coherence function with respect to a delay between two optical waves is proposed and demonstrated by using a distributional Rayleigh speckle analysis based on C-OFDR. This technique allows us to estimate both the coherence time of the laser and that of the spectral profiles from the measured amplitude of the coherence function, if the symmetry of the spectrum can be assumed. The spectral width obtained in the experiment agrees roughly with that obtained using a delayed self-heterodyne method.
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http://dx.doi.org/10.1364/OE.19.019790DOI Listing
October 2011

Invited commentary.

Authors:
Masaaki Inoue

Ann Thorac Surg 2011 Apr;91(4):1072

Department of Thoracic Surgery, Shin-Kokura Hospital, 1-3-1 Kanada, Kokurakita-ku, Kitakyushu, Japan 803-8505.

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http://dx.doi.org/10.1016/j.athoracsur.2011.01.047DOI Listing
April 2011

[Treatment recommendations for adrenal metastasis of non-small cell lung cancer].

Kyobu Geka 2010 Dec;63(13):1101-6; discussion 1106-8

Department of Thoracic Surgery, Niigata Rosai Hospital, Joetsu, Japan.

To evaluate the optimum treatment strategy for metastatic adrenal tumors derived from non-small cell lung cancer (NSCLC), we retrospectively analyzed 17 consecutive cases (8 resection cases: 4 synchronous and 4 metachronous: 9 non-resection cases: 3 synchronous and 6 metachronous) who received surgical resection for NSCLC. The patients included 12 males and 5 females with a mean age of 63.9 years. Of these, 9, 3, 2, 2, and 1 patient (s) were diagnosed as having adenocarcinoma, squamous cell carcinoma, pleomorphic carcinoma, large cell carcinoma, and adenosquamous cell carcinoma, respectively. The mean interval after lung resection and treatment of metachronous adrenal metastasis was 9.9 months. The mean time to progression from treatment of metachronous adrenal metastasis to disease progression was 8.9 months. A survival analysis showed no significant prognostic difference between the patient age, gender, pathological stage, synchronous/metachronous classification, CEA, and site of metastases. However, patients who received an adrenalectomy had a more favorable prognosis. The 2-year survival of patients following resection versus those who did not undergo a resection for adrenal metastasis was 62.5 and 22.8%, respectively. These data indicate that metastatic adrenal tumors should be resected if the patient can tolerate surgery after appropriate selection.
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December 2010

A randomized phase II trial of adjuvant chemotherapy with bi-weekly carboplatin plus paclitaxel versus carboplatin plus gemcitabine in patients with completely resected non-small cell lung cancer.

Anticancer Res 2010 Nov;30(11):4695-9

Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

Background: The benefits of adjuvant chemotherapy for completely resected non-small cell lung cancer (NSCLC) have been demonstrated using mainly cisplatin (CDDP)-based chemotherapeutic regimens. However, treatment-related deaths sometimes occur. Therefore, the development of a safer regimen is necessary.

Patients And Methods: The patients were randomized to either carboplatin (CBDCA) area under the curve (AUC) 3 and paclitaxel (PTX) 90 mg/m(2) (PCb arm) or CBDCA (AUC3) plus gemcitabine (GEM) (1000 mg/m(2)) (GCb arm) every 2 weeks for 8 cycles after surgery. The primary endpoint was the compliance with the regimen, while the secondary endpoints were safety and toxicity.

Results: A total of 75 patients were enrolled in a multi-institutional study. Twenty-one out of 39 patients (54%) in the PCb arm and 25 of 36 patients (69%) in the GCb arm completed 8 cycles, and 59% in the PCb arm and 81% in the GCb arm completed ≥6 cycles. The predominant toxicity was neutropenia. Non-hematological adverse effects were infrequent and no treatment-related death was registered. The estimated disease-free survival and overall survival at 2 years were 70.8% and 66.3% in the PCb and 91.4% and 79.1% in the GCb arm, respectively.

Conclusion: This adjuvant bi-weekly scheduled chemotherapy resulted in good compliance in both arms, and the regimen was feasible, with acceptable levels of toxicity in completely resected Japanese NSCLC patients. Therefore, these regimens represent a new treatment option suitable for outpatients with completely resected NSCLC.
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November 2010

Comparison of lung cancer cell lines representing four histopathological subtypes with gene expression profiling using quantitative real-time PCR.

Cancer Cell Int 2010 Jan 21;10. Epub 2010 Jan 21.

Department of Chemistry and Biological Science, School of Science and Engineering, Aoyama Gakuin University, Kanagawa 229-8558, Japan.

Background: Lung cancers are the most common type of human malignancy and are intractable. Lung cancers are generally classified into four histopathological subtypes: adenocarcinoma (AD), squamous cell carcinoma (SQ), large cell carcinoma (LC), and small cell carcinoma (SC). Molecular biological characterization of these subtypes has been performed mainly using DNA microarrays. In this study, we compared the gene expression profiles of these four subtypes using twelve human lung cancer cell lines and the more reliable quantitative real-time PCR (qPCR).

Results: We selected 100 genes from public DNA microarray data and examined them by DNA microarray analysis in eight test cell lines (A549, ABC-1, EBC-1, LK-2, LU65, LU99, STC 1, RERF-LC-MA) and a normal control lung cell line (MRC-9). From this, we extracted 19 candidate genes. We quantified the expression of the 19 genes and a housekeeping gene, GAPDH, with qPCR, using the same eight cell lines plus four additional validation lung cancer cell lines (RERF-LC-MS, LC-1/sq, 86-2, and MS-1-L). Finally, we characterized the four subtypes of lung cancer cell lines using principal component analysis (PCA) of gene expression profiling for 12 of the 19 genes (AMY2A, CDH1, FOXG1, IGSF3, ISL1, MALL, PLAU, RAB25, S100P, SLCO4A1, STMN1, and TGM2). The combined PCA and gene pathway analyses suggested that these genes were related to cell adhesion, growth, and invasion. S100P in AD cells and CDH1 in AD and SQ cells were identified as candidate markers of these lung cancer subtypes based on their upregulation and the results of PCA analysis. Immunohistochemistry for S100P and RAB25 was closely correlated to gene expression.

Conclusions: These results show that the four subtypes, represented by 12 lung cancer cell lines, were well characterized using qPCR and PCA for the 12 genes examined. Certain genes, in particular S100P and CDH1, may be especially important for distinguishing the different subtypes. Our results confirm that qPCR and PCA analysis provide a useful tool for characterizing cancer cell subtypes, and we discuss the possible clinical applications of this approach.
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http://dx.doi.org/10.1186/1475-2867-10-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817686PMC
January 2010

DNA modifications by the omega-3 lipid peroxidation-derived mutagen 4-oxo-2-hexenal in vitro and their analysis in mouse and human DNA.

Chem Res Toxicol 2010 Mar;23(3):630-6

Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.

4-Oxo-2-hexenal (4-OHE), which forms a 2'-deoxyguanosine (dG) adduct in a model lipid peroxidation system, is mutagenic in the Ames test. It is generated by the oxidation of omega-3 fatty acids and is commonly found in dietary fats, such as fish oil, perilla oil, rapeseed oil, and soybean oil. 4-OHE also forms adducts with 2'-deoxyadenosine (dA), 2'-deoxycytidine (dC), and 5-methyl-2'-deoxycytidine (5-Me-dC) in DNA. In this study, we characterized the structures of these adducts in detail. We measured the amounts of 4-OHE-DNA adducts in mouse organs by LC/MS/MS, after 4-OHE was orally administered to mice. The 4-OHE-dA, 4-OHE-dC, 4-OHE-dG, and 4-OHE-5-Me-dC adducts were detected in stomach and intestinal DNA in the range of 0.25-43.71/10(8) bases. After the 4-OHE administration, the amounts of these DNA adducts decreased gradually over 7 days. We also detected 4-OHE-dC in human lung DNA, in the range of 2.6-5.9/10(9) bases. No difference in the 4-OHE adduct levels was detected between smokers and nonsmokers. Our results suggest that 4-OHE-DNA adducts are formed by endogenous as well as environmental lipid peroxides.
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http://dx.doi.org/10.1021/tx9003819DOI Listing
March 2010

Gefitinib and a ventriculo-peritoneal shunt to manage carcinomatous meningitis from non-small-cell lung cancer: report of two cases.

Surg Today 2009 28;39(7):598-602. Epub 2009 Jun 28.

Department of Thoracic Surgery, Niigata Rosai Hospital, Joetsu, Niigata, Japan.

The prognosis of patients with carcinomatous meningitis from non-small-cell lung cancer (NSCLC) remains poor, and the available treatment options for the lung cancer do not relieve the severe symptoms of this sequela. We report the successful treatment of two cases of carcinomatous meningitis caused by NSCLC, using gefitinib and a ventriculo-peritoneal (V-P) shunt. The first patient was a 43-year-old woman with pT1N0M0 adenocarcinoma. Multiple brain and vertebral metastases were found 13 months after surgery. She had undergone gamma-knife radiosurgery for the brain metastases, radiotherapy for the vertebral metastases, and two regimens of systemic chemotherapy, before carcinomatous meningitis was diagnosed. She was given gefitinib, and then a V-P shunt was placed. She continued to take gefitinib and was free of subjected symptoms for 5 months until she died. The second patient was a 64-year-old woman with cT4N0M0 adenocarcinoma. After local chemotherapy using cisplatin and OK-432 for carcinomatosis pleuritis and two regimens of systemic chemotherapy, carcinomatous meningitis was detected. A V-P shunt was placed, and she was sequentially given gefitinib. At her 15-month follow-up, she was free of symptoms of carcinomatous meningitis. No adverse effects or shunt problems were detected in either patient. This therapeutic modality may liberate carcinomatous meningitis patients with severe symptoms from hospitalization and improve their quality of life.
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http://dx.doi.org/10.1007/s00595-008-3909-1DOI Listing
September 2009

Successful treatment of sclerosing mediastinitis with a high serum IgG4 level.

Gen Thorac Cardiovasc Surg 2007 Oct;55(10):431-3

Department of Chest Surgery, Niigata Rosai Hospital, 1-7-12 Touncho, Joetsu, Niigata, Japan.

Sclerosing mediastinitis is not a common condition in the thoracic cavity and is difficult to cure. Several medications have been used; however, most of the cases do not achieve satisfactory results, and the most successful treatment is operative resection. We report the first case of IgG4-related sclerosing mediastinitis that showed IgG4-positive plasma cells infiltrated into the fibrous tissue and a high serum IgG4 level. The patient clearly showed remission of the symptoms after steroid therapy. Our findings suggest that the serum IgG4 level is a good selection indicator for steroid therapy in sclerosing mediastinitis.
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http://dx.doi.org/10.1007/s11748-007-0154-2DOI Listing
October 2007

Comparison of newly developed inhalation anesthesia system and intraperitoneal anesthesia on the hemodynamic state in mice.

Biol Pharm Bull 2007 Sep;30(9):1716-20

Department of Integrative Physiology & Bio-System Control, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.

KNI-472 is the first anesthetic system for mice and rats to incorporate a ventilator. It consists of a newly developed syringe pump-type vaporizer and gas monitor that can deliver accurate concentrations of anesthetic gas at an extremely low airflow. In this study, we compared the hemodynamic effects of isoflurane anesthesia using KNI-472 and intraperitoneal pentobarbital anesthesia. In the isoflurane anesthetic group, Institute of Cancer Research (ICR) mice were anesthetized with 5% isoflurane, followed by endotracheal intubation. Subsequently, they were ventilated mechanically, and anesthesia was maintained with 2% isoflurane for a 60-min period using KNI-472. In the pentobarbital anesthetic group, the ICR mice were anesthetized by an intraperitoneal injection of sodium pentobarbital (70 mg/kg). In isoflurane anesthesia, the heart rate (HR) and mean blood pressure (MBP) were stable. In contrast, in pentobarbital anesthesia, MBP decreased in the first stage after the initiation of anesthesia, after which it gradually increased. The intra-group variability in the estimated skin blood flow (SBF) was higher in the pentobarbital anesthesia than that in the isoflurane anesthesia. The PaO(2) and PaCO(2) values at 15 min after the initiation of pentobarbital anesthesia revealed hypoxia and hypercapnia compared with isoflurane anesthesia. In this study, isoflurane anesthesia using KNI-472, unlike pentobarbital anesthesia, did not induce changes in MBP, SBF, or blood gases. The changes induced by pentobarbital anesthesia were attributed to a change in the depth of anesthesia with time. These results indicate that inhalation anesthesia using KNI-472 is suitable in research on the hemodynamic state in mice.
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http://dx.doi.org/10.1248/bpb.30.1716DOI Listing
September 2007

NARCOBIT: a newly developed inhalational anesthesia system for mice.

Exp Anim 2007 Apr;56(2):131-7

Department of Integrative Physiology & Bio-System Control, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.

NARCOBIT is the first anesthetic system for mice and rats to incorporate a ventilator. Therefore, it is expected to improve the reliability of mice and rat experiments by accurately controlling and maintaining the depth of anesthesia. In this study, we used NARCOBIT for inducing inhalational anesthesia in mice and evaluated the changes in their hemodynamic parameters. ICR mice were anesthetized with 5% isoflurane and room air, followed by endotracheal intubation. Subsequently, they were mechanically ventilated, and anesthesia was maintained by 2% isoflurane for a 60-min period (maintenance state) using NARCOBIT. In study 1, the heart rate (HR) and mean arterial blood pressure (MAP) were measured. The skin blood flow (SBF) from the hind legs was continuously measured during the maintenance state. Subsequently, the concentration-dependent effects of isoflurane on MAP were examined. In study 2, blood samples were obtained from the abdominal aorta for blood gas analysis. The HR and MAP decreased after anesthesia but were stable during the maintenance state. Decreased MAP and concentration-dependent effects of isoflurane were observed. The SBF increased slightly during the maintenance state but this increase was insignificant. The blood gas analysis showed neither hypoxia nor hypercapnia. Since the use of NARCOBIT enables the anesthetic concentration of isoflurane to be easily changed, a suitable anesthesia depth can be obtained for experimental purposes. Therefore, we conclude that NARCOBIT can be used for providing inhalational anesthesia to mice.
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http://dx.doi.org/10.1538/expanim.56.131DOI Listing
April 2007

Leiomyoma originating from the extrapleural tissue of the chest wall.

Jpn J Thorac Cardiovasc Surg 2006 Jun;54(6):242-5

Department of Chest Surgery, Labor Welfare Niigata Rosai Hospital, Joetsu, Japan.

We describe a rare case of leiomyoma of the chest wall in a 55-year-old female. Computed tomography showed a well-circumscribed neoplasm with a diameter of 2 cm in the right chest wall. The tumor was excised with video-assisted thoracic surgery. Histopathology confirmed that the tumor was leiomyoma arising from the microvascular smooth muscle in the chest wall. We present the immunohistochemical profiles of the tumor in detail, critically reviewing the previously reported cases.
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http://dx.doi.org/10.1007/pl00022244DOI Listing
June 2006

MDCT of hypervascular hepatocellular carcinomas: a prospective study using contrast materials with different iodine concentrations.

AJR Am J Roentgenol 2005 May;184(5):1535-40

Department of Radiology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.

Objective: The objective of our study was to investigate the effect of different iodine concentrations in contrast materials on the depiction of hypervascular hepatocellular carcinomas (HCCs) by MDCT.

Subjects And Methods: This prospective study involved 100 consecutive patients with chronic liver disease, including 27 patients with hypervascular HCCs. The first 50 patients received 100 mL of iopamidol at a concentration of 370 mg I/mL (group A) and the subsequent 50, 100 mL at 300 mg I/mL (group B); in both groups, the contrast material was administered at a rate of 3.0 mL/sec. Unenhanced scanning and four-phase enhanced scanning at 25, 40, 60, and 180 sec after the start of contrast injection were performed. The enhancement of the aorta, liver, and portal vein was measured during each phase. In addition, tumor-to-liver contrast was calculated for the 27 patients with hypervascular HCCs. Of the 27 patients with hypervascular HCCs, 15 were in group A and 12 were in group B.

Results: During all phases, aortic enhancement was significantly greater in group A than group B (p < 0.01). Hepatic enhancement was significantly greater in group A than group B at 60 and 180 sec (both p < 0.01). There was no significant difference in hepatic enhancement between the two groups at 25 and 40 sec. Tumor-to-liver contrast was significantly greater in group A than group B during the late arterial phase (40 sec, p = 0.02), although there was no significant difference at 25, 60, and 180 sec.

Conclusion: Contrast materials with higher iodine concentration are more effective for depicting hypervascular HCCs on MDCT during the late arterial phase.
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http://dx.doi.org/10.2214/ajr.184.5.01841535DOI Listing
May 2005

Moderate versus high concentration of contrast material for aortic and hepatic enhancement and tumor-to-liver contrast at multi-detector row CT.

Radiology 2004 Dec 14;233(3):682-8. Epub 2004 Oct 14.

Department of Radiology, Kinki University School of Medicine, 2-23 Ono-higashi, Osaka-Sayama, Osaka 589-8511, Japan.

Purpose: To prospectively evaluate aortic and hepatic enhancement and depiction of hypervascular hepatocellular carcinoma (HCC) between two contrast materials with moderate and high iodine concentrations when administered at same iodine dose and injection duration at multi-detector row helical computed tomography (CT).

Materials And Methods: Institutional review board approval and informed patient consent were obtained. One hundred eighty-six patients were studied, and 67 patients with hypervascular HCC were identified. Ninety-four patients were assigned to receive iohexol 350 (mg iodine per milliliter) with protocol A; 92, iohexol 300 with protocol B. In both protocols, iohexol with same iodine load per weight (518 mg/kg) was administered with same injection duration (25 seconds). Multiphase CT scanning was started 10, 20, 50, and 180 seconds after the trigger (threshold level set at increase of 100 HU over baseline CT number of aorta). Enhancement of aorta and liver was measured in 186 patients. Tumor-to-liver contrast was measured in 67 patients with hypervascular HCC. Statistical analysis was performed with Mann-Whitney U test.

Results: Medians of aortic enhancement during four phases were 325, 185, 112, and 69 HU with protocol A. Corresponding values were 344, 266, 121, and 73 HU with protocol B. During all phases, aortic enhancement was significantly higher with protocol B (P = .046, P < .001, P < .001, and P = .002). Hepatic enhancement during four phases was 6, 21, 48, and 34 HU with protocol A. Corresponding values were 3, 17, 47, and 35 HU with protocol B. Hepatic enhancement was significantly higher with protocol A during first and second phases (P < .001 for both), although there was no significant difference between protocols during third and fourth phases (P = .778 and P = .178, respectively). Medians of tumor-to-liver contrast during four phases were 22, 34, 0.5, and -1.1 HU with protocol A. Corresponding values were 23, 45, 0, and -8.6 HU with protocol B. Tumor-to-liver contrast was significantly higher with protocol B during second phase (P = .049), although there was no difference between protocols during other phases.

Conclusion: When total iodine dose was adjusted to body weight and injection duration was fixed, rapid administration of moderate concentration of contrast material was more effective for depiction of hypervascular HCC than was high concentration of contrast material.
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http://dx.doi.org/10.1148/radiol.2333031617DOI Listing
December 2004

Dynamic multidetector CT of breast tumors: diagnostic features and comparison with conventional techniques.

AJR Am J Roentgenol 2003 Sep;181(3):679-86

Department of Radiology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.

Objective: We sought to analyze the features of breast tumors as revealed on dynamic multidetector CT (MDCT), to develop descriptors for these features, and to compare the performance of MDCT with the performance of other techniques used in the depiction of tumors. SUBJECTS AND METHODS. MDCT was performed in 149 women with suspected breast tumors, and 173 breast lesions were detected. These breast lesions were classified as either mass or nonmass enhancing lesions. For mass lesions, the margin, shape, and enhancement patterns were evaluated. For nonmass enhancing lesions, the distribution of enhancement and the types of time-density curve patterns were evaluated. MDCT was compared with mammography and sonography as a method of revealing breast tumors.

Results: Of the 173 breast lesions detected, 150 were mass lesions, 131 (87%) of which were malignant. Of the 23 nonmass enhancing lesions, 21 (91%) were malignant. The most highly predictive features for lesion malignancy were an irregular margin (100%), an irregular shape (99%), and rim enhancement (100%). Similar features were the most accurate signs of malignancy--a spiculated and irregular margin (90%). On time-density curves, the washout and plateau patterns showed high positive predictive value (93%) and sensitivity (91%) for malignancy. However, these patterns had low negative predictive value (42%) and specificity (48%). Seven breast lesions that could not be detected on mammography or sonography were identified on MDCT. MDCT more accurately revealed the margin of the tumor invasion in 11 breast tumors than did mammography or sonography.

Conclusion: The features revealed on MDCT can help to distinguish benign lesions from carcinomas. MDCT can add to the data obtained with mammography or sonography in patients with suspected breast tumors.
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http://dx.doi.org/10.2214/ajr.181.3.1810679DOI Listing
September 2003

Decline of nuclear and mitochondrial oxidative base excision repair activity in late passage human diploid fibroblasts.

DNA Repair (Amst) 2003 Jun;2(6):673-93

Department of Microbiology and Molecular Genetics, The Markey Center for Molecular Genetics, The University of Vermont, 95 Carrigan Drive, Stafford Hall, Burlington, VT 05405-0068, USA.

There are numerous studies documenting the increase of oxidative DNA damage in the nuclei and mitochondria of senescing cells as well as in tissues of aging animals. Here, we show that in IMR 90 human diploid fibroblasts, DNA repair activity is robust in both nuclear and mitochondrial extracts, however, the levels of activity differed against the three substrates tested. In extracts, cleavage of the 8-oxoguanine substrate, and to a lesser extent the dihydrouracil-containing substrate, occurred in a concerted reaction between the DNA glycosylases and the second enzyme in the reaction, hAPE. Cleavage of both the furan and the dihydrouracil-containing substrates was unchanged when nuclear extracts from early and late passage cells were compared. However, cleavage of the 8-oxoguanine substrate was substantially reduced in the nuclear extracts from late passage cells and significantly reduced transcription from the hOGG1 gene was observed. When mitochondrial extracts were examined, activity on all three substrates was significantly reduced, with the reduction in hAPE activity being the most marked. The reduction in cleavage of the furan substrate was not simply due to inactive mitochondrial AP endonuclease but a substantially reduced amount of hAPE protein; transcription from the hAPE gene was also reduced. Confocal microscopic analysis confirmed that hAPE was present in the mitochondria of early passage cells but greatly reduced in the mitochondria of late passage cells. Cytoplasmic extracts from late passage fibroblasts also showed reduced activity with all three substrates suggesting that the residual hAPE, and activities that recognized dihydrouracil, were preferentially targeted to the nuclei. Taken together the data support the concept that the increase in oxidative damage in the mitochondrial DNA of senescing cells and tissues from aging animals is due to reduced base excision repair activity.
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http://dx.doi.org/10.1016/s1568-7864(03)00006-5DOI Listing
June 2003
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